P487: MIDOSTAURIN PLASMA EXPOSURE IN PATIENTS WITH FLT3-MUT ACUTE MYELOID LEUKEMIA UNDERGOING POSACONAZOLE PROPHYLAXIS DURING INDUCTION TREATMENT: A PROSPECTIVE MULTICENTRE STUDY FROM THE SEIFEM GROUP
Authors: Francesco Marchesi, Pierantonio Menna, Chiara Cattaneo, Anna Candoni, Mario Delia, Gianpaolo Nadali, Crescenza Pasciolla, Salvatore Perrone, Luisa Verga, Daniele Armiento, Maria Ilaria DEL Principe, Nicola Stefano Fracchiolla, Emanuela Salvatorelli, S Lupisella, Irene Terrenato, Alessandro Busca, Livio Pagano
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: The approval of midostaurin, in combination with standard “7 + 3” chemotherapy, has recently changed the scenario of induction treatment in patients affected by FLT3-mut AML. Midostaurin is a substrate of CYP3A4, which converts it into O-demethylated or hydroxylated metabolites (CGP62221 or CGP52421, respectively). FLT3-mut AML patients should be exposed to concomitant posaconazole (PCZ) and midostaurin. However, PCZ is a strong CYP3A4 inhibitor that could also inhibit midostaurin metabolism resulting in its unnecessary overexposure. Recently published data showed significant increase of midostaurin plasma concentrations in patients who had concomitantly received PCZ. A post-hoc analysis from the RATIFY trial showed that in patients concomitantly treated with midostaurin and strong CYP3A4 inhibitors only emerged a shorter time of occurrence of grade 3 or 4 toxicities for which no dose adjustment was required. However further confirmations are needed. Aims: We planned a prospective multicenter study within the SEIFEM (Sorveglianza Epidemiologica InFezioni nelle EMopatie) group aiming to monitor midostaurin plasma exposure in FLT3-mut AML patients concomitantly exposed to PCZ during induction chemotherapy. Methods: The study enrolled 37 adult patients with newly diagnosed FLT3-mut AML suitable for induction treatment with CHT (“7 + 3” or “5 + 2”) plus midostaurin. All blood samples were drawn at day +8 and +21 from the beginning of chemotherapy before, at 3 and 12 hours from midostaurin administration. Midostaurin, its metabolites and PCZ were measured by validated quantitative liquid chromatography tandem mass spectrometry methods. Results: At day+8 patients treated with PCZ were exposed to a total plasma exposure of midostaurin-related material (defined by the sum of midostaurin and its metabolites) similar to that of patients who did not receive PCZ (Figure 1, Panel A). Moreover, both patient populations exhibited the same relative plasma exposure to midostaurin and its metabolites (defined as the percent ratio of midostaurin or metabolites to total exposure) (Figure 1, Panel B). However, at day +21 midostaurin plasma exposure was significantly higher in patients treated with midostaurin and PCZ (P=0.001, Figure 1, Panels C). Moreover, these patients were exposed to approximatively 50% increase of midostaurin relative plasma exposure that was consistent of an approximatively 50% decreased relative plasma exposure to metabolites (P=0.002, Figure 1, Panel D). The total plasma exposure ratio in PCZ-treated/untreated patients was of 1.78 (P=0.008). In all patients of PCZ group, PCZ reached the target plasma concentration of >0.7 μg/mL. Twenty-nine patients achieved a complete remission, with no significant differences between patients exposed or not to PCZ (84% vs 81%, respectively). No significant differences in terms of midostaurin-related AEs, midostaurin discontinuation or dose reduction were observed between the two groups. Toxicity was responsible for midostaurin discontinuation/dose reduction in 4 patients (21%) during PCZ prophylaxis and in 3 patients not exposed to PCZ (19%). We observed three cases of invasive fungal infections (8.5%), once again with no differences between the two groups. Summary/Conclusion: Our study suggest that the concomitant administration of PCZ and midostaurin results effective and safe for FLT3-mut AML patients. A pharmacokinetic guided approach by measuring plasma levels of both midostaurin and PCZ, in particular for those patients experiencing toxicities, might could support haematologists towards a precision medicine.Keywords: flt3 inhibitor, Acute myeloid leukemia, Drug interaction